Synergistic diuretic composition



United States Patent 3,323,997 SYNERGISTIC DIURETIC COMPOSITION John H. Laragh, New York, N.Y., assiguor to Merck & Co., Inc, Rahway, N.J., a corporation of New Jersey No Drawing. Filed July 16, 1964, Ser. No. 383,237 8 Claims. (Cl. l6765) This invention relates to pharmaceutical formulations and particularly to a preparation which has advantageous diuretic properties.

Diuretics are valuable therapeutic agents as they are useful in the treatment of cardiovascular and renal diseases. Their use is indicated in the management of all types and grades of severity of congestive heart failure in which diuretic therapy is required. Due to the resulting water loss, dramatic improvement is noted in peripheral and pulmonary edema, dyspnea, orthopnea, cough ascites and pleural effusion.

The diuretics also provide effective diuretic therapy in various forms of renal edema, e.g., edema associated with nephrosis and certain types of nephritis. Their administration results in prompt excretion of retained fluid and electrolytes with consequent benefit to the patient.

One of the newer diuretics is ethacrynic acid which is a methylenebutyryl phenoxyacetic acid. Chemically, it is 2,3-dichloro-4- Z-methylenebutyryl -phenoxyacetic acid. Its use is reported in an article entitled, Methylenebutyryl Phenoxyacetic Acid, by Dr. Paul J. Cannon et. al. in the J. A. M. A., Sept. 14, 1963, Vol. 185, pp. 854863. The preparation of it and related compounds is reported in an article by M. M. Schultz et. al. entitled, Beta-Unsaturated Ketone Derivatives of Aryloxyacetic Acids, New Class of Diuretics, J. Med. Pharm. Chem, 5:660, 1962. The administration of ethacrynic acid to patients sometimes results in such a prodigious diuresis and consequent loss of hydrogen ions that a hypochloremic alkalosis results. The consequent alkaline condition of the patient is an acid-base imbalance that should not be allowed to persist.

In accordance with the present invention it has been found that the coadministration with ethacrynic acid of a diuretic which has a carbonic anhydrase inhibitorary action will prevent or at least minimize the emergence of the ethacrynic acid induced alkalosis. Moreover, this coadministration results in an increased diuresis which could not be anticipated and which makes possible the administration of a smaller amount of ethacrynic acid than would be required if the latter were used.

The carbonic anhydrase inhibitor which may be used may be one of the compounds disclosed in United States Patent Nos. 2,554,816 and 2,835,702. A preferred compound disclosed in Patent No. 2,554,816 is that of Example 4, which is known as acetazolamide and is sold under the trademark Diamox. Instead of acetazolamide, the invention contemplates the use of a heterocyclic sulfonamide compound having the general formula:

in which R and R are members of the group consisting of hydrogen, alkyl, alkaryl and aryl radicals and X is a heterocyclic radical of the group consisting of triazole, thiadiazole', tetrazole and pyridotriazole radicals.

A preferred compound disclosed in Patent No. 2,835,702 is that of Example 1, which is known as dichlorophenamide and is sold under the trademark Daranide. Instead of dichlorophenamide, the invention contemplates the use of benzene disulfonamide compound having the general formula:

3,323',997 Patented June 6, 1967 in which X is selected from the group consisting of chlorine and bromine atoms.

Although ethacrynic acid is the preferred phenoxyacetic acid type diuretic the invention contemplates the use of a compound disclosed in South Africa Patent No. 60 of October 30, 1962 or Belgium Patent No. 612,755 of July 17, 1962 and having the general formula:

where each of R, R and R respectively is selected from the group consisting of Hydrogen; Halogen or halogen-like radicals; Hydroxyl; Lower aliphatic, lower aliphatic-oxy or lower Aliphatic-thio, straight or branched chain, saturated or unsaturated, and unsubstituted or substituted, the substituent gr0up(s) being alkyl, amino, halogen-like, carboxyl or substituted carboxyl, cyano, hydroxyl, alkyl thio, aryl thio, arylsulfonyl, alkylsulfonyl, nitro, and the like Alicyclic, either unsubstituted or substituted, the substituent groups being the same as those described above for the aliphatic group; Aryl or aryl-oxy or aryl-thio, especially and phenyl, phenoxy or phenylthio wherein the aryl-(phenyl)-moiety can be unsubstituted or a substituent can be attached to one or more of its carbon atoms selected advantageously from lower, straight or branched chainalkyl, alkoxy, alkylthio, hydroxyl, halogen or halogen-like; Arylaliphatic, especially a mononuclear-arylaliphatic, advantageously phenalkyl which can be attached through an oxygen or a sulfur atom to the grouping and which is either unsubstituted or substituted in the aryl and/ or alkyl portions by substituents of the type hereinbefore described;

Cyano; and wherein R and R additionally can be linked together to form preferably a 5 to 6 carbon ring with the carbons to which they are attached;

each of R R and R is selected from the group consisting of Hydrogen, Halogen or halogen-like, Lower aliphatic straight or branched chain Lower aliphatic-oxy or lower aliphatic-thio straight or branched chain, unsubstituted or havinga substituent of the type described above for attachment to the lower aliphatic group; and wherein the lower aliphatic-oxy or lower aliphatic-thio is advantageously lower alkoxy or loweralkylthio, unsubstituted or substituted, as for example,

carboxyalkoxy carboxyalkylthio, and the like;

Aliphaticsulfonyl, especially an alkylsulfonyl;

hydroxyl;

nitro;

amino;

carboxy or substituted carboxy, especially carbamoyl and N-substituted carbamoyl;

Aryl, especially phenyl,

unsubstituted or substituted as described above for attachment to aryl (phenyl)moieties; and where R and R and/ or R and R can additionally be linked together to form, with the ring, carbons to which they are attached, a 5- or 6-mem'bered carbocyclic ring;

A represents oxygen of sulfur which can be oxidized to the sulfoxide or sulfone.

B represents a divalent aliphatic,

aromatic or aliphatic-aromatic group, preferably a straight or branched chain lower aliphatic group which can contain oxygen or sulfur atoms as part of the aliphatic chain,

a phenyl-lower alkyl, or

a phenyl group x represents Hydroxyl or a hydroxyl in which the hydrogen has been replaced with a salt-forming element or radical, such as sodium, potassium, calcium and the like or an amino group alkoxyl unsubstituted or substituted, the substituent(s) being dialiphatic amino and the like Amino,

In the above definitions and in the claims, the term halogen embraces halogen-like groups and represents chlorine, bromine, iodine, fluorine, halomethyl especially trichloromethyl, trifluoromethyl and the like. Also in the above definitions and in the claims, the term amino should be understood to embrace primary, secondary and tertiary amino groups; including N-containing heterocycles as piperidyl, pyrrolidyl, morpholinyl, N-lower alkyl-piperazinyl and the like, as well as the usual pharmaceutically acceptable salts thereof.

The composition of the invention utilizes the ingredients within the following ranges, per unit dose.

Permissive Preferred Range, mg. Range, mg.

Phenoxyacctic acid compound 10 to 25 to 50. Benzene disulfonamidc compound 10 to 100. 25 to 50. Phenoxyacetic acid compound. 10 to 100. 25 to 50. Heteroeyelie sull'onamide compound 100 to 1,000.... 250 to 500.

Suitable compositions are the following:

Example 1 A No. 3 capsule contains 10 mg. of ethacrynic acid, 10 mg. of dichlorphenamide, 1 mg. of a lubricating powder such as talc and 200 mg. of a filler such as lactose. One would be taken 3 or 4 times daily giving a daily dose of 30 to 40 mg. of each drug.

Example 2 A No. 3 capsule contains 50 mg. of ethacrynic acid, 50 mg. of dichlorphenamide, 3 mg. of a lubricating powder such as magnesium stearate and mg. of a filler such as calcium phosphate dibasic. One would be taken 3 or 4 times daily giving a daily dose of to 200 mg. of each drug.

Example 3 A No. 3 capsule contains 100 mg. of ethacrynic acid, 100' mg. of dichlorphenamide, 2 mg. of a lubricating powder such as above and 25 mg. of a filler such as above. One would be taken 3 or 4 times daily giving a daily dose of 300 to 400 mg. of each drug.

Example 4 A No. 3 capsule contains 50 mg. of ethacrynic acid, 25 mg. of dichlorphenamide, 2 mg. of a lubricating powder and a filler, q.s. One would be taken 3 or 4 times daily giving a daily dose of 150 to 200 mg. of ethacrynic acid and 75 to 100 mg. of dichlorphenamide.

Example 5 A No. 3 capsule contains 25 mg. of ethacrynic acid, 50 mg. of dichlorphenamide, 2 mg. of a lubricating powder and a filler, q.s. One would be taken 3 or 4 times daily giving a daily dose of 75 to 100 mg. of ethacrynic acid and 150 to 200 mg. of dichlorphenamide.

Example 6 For the ethacrynic acid in Examples 1 to 6 is substituted a like amount of one of the above identified phenoxyacetic acid compounds and for the dichlorphenamide is substituted a like amount of one of the above identified benzene disulfonamide compounds.

Example 7 A No. 2 capsule contains 10 mg. of ethacrynic acid, 100 mg. of acetazolamide, 2 mg. of a lubricating powder and 100 mg. of a filler. One would be taken 3 or 4 times daily giving a daily dose of 30 to 40 mg. of ethacrynic acid and 300 to 400 mg. acetazolamide.

Example 8 A No. 1 capsule contains 25 mg. of ethacrynic acid, 250 mg. of acetazolamide, 3 mg. of a lubricating powder and 50 mg. of a filler. One would be taken 3 or 4 times daily giving a daily dose of 75 to 100 mg. of ethacrynic acid and 750 to 1000 mg. of acetazolamide.

Example 9 A No. 0 capsule contains 50 mg. of ethacrynic acid, 500 mg. of acetazolamide, 3 mg. of a lubricating powder and 50 mg. of a filler. One would be taken 3 or 4 times daily giving a daily dose of 150 to 200 mg. of ethacrynic acid and 1500 to 2000 mg. of acetazolamide.

Example Two No. 0 capsules contain 100 mg. of ethacrynic acid, 1000 mg. of acetazolamide, 4 mg. of a lubricating powder and 50 mg. of a filler. Two would be taken 3 or 4 times daily giving a daily dose of 300 to 400 mg. of ethacrynic acid and 3000 to 4000 mg. of acetazolamide.

Example 11 A No. 2 capsule contains 25 mg. of ethacrynic acid, 500 mg. of acetazolamide, 2 mg. of a lubricating powder and 50 mg. of a filler. One would be taken 3 or 4 times daily giving a daily dose of 75 to 100 mg. of ethacrynic acid and 1500 to 2000 mg. of acetazolamide.

Example 12 A No. 1 capsule contains 50 mg. of ethacrynic acid, 250 mg. of acetazolamide, 2 mg. of a lubricating powder and 50 mg. of a filler. One would be taken 3 or 4 times daily giving a daily dose of 150 to 200 mg. of ethacrynic acid and 750 to 2000 mg. of acetazolamide.

Example 13 For the ethacrynic acid in Examples 7 to 12 is substituted a like amount of one of the above identified phenoxyacetic acid compounds and for the acetazolamide is substituted a like amount of one of the above identified heterocyclic sulfonamide compounds.

Example 14 Tablets are made by combining the following ingredients in such quantities that each tablet contains:

These ingredients, With the exception of the lubricating and disintegrating agents, are milled and dried and then these omitted agents are added. This mixture is then compressed into tablets.

Example 15 Tablets, corresponding in their drug content, to Examples 2 to 13 are made by following the teaching of Example 14, the ingredients other than the drugs being varied in accordance with common pharmaceutical practices.

Example 16 The active drugs of Examples 1 to 13, where they total less than 500 mg, are put into suppositories having the following base:

Mg. Polyethylene glycol 1000 570 Polyethylene glycol 4000 820 If the drugs add up to more than 500 mg, two suppositories should be made up, using the same ratio of the glycols. If the drugs add up to more than 500 mg. two suppositories should be made up, using the same ratio of the glycols.

What is claimed is:

1. The method of achieving diuresis in a person suffering from water retention, which involves administering to that person (A) from 10 to mg. of ethacrynic acid and coadministering substantially simultaneously therewith a compound selected from the class consisting of (B) 10 to 100 mg. of dichlorphenamide and (C) from 100 to 1000 mg. of acetazolamide.

2. The method of achieving diuresis in a person suffering from water retention, according to claim 1 which involves administering to that person (A) 25 to 50 mg. of ethacrynic acid and coadministering substantially simultaneously therewith a compound selected from the class consisting of (B) 25 to 50 mg. of dichlorphenamide and (C) from 250 to 500 mg. of acetazolamide.

3. The method of achieving diuresis in a person sufiering from water retention, according to claim 1 which involves administering to that person 50 mg. of ethacrynic acid and 50 mg. of dichlorophenamide.

4. The method of achieving diuresis in a person suffering from water retention, according to claim 1 which comprises administering to that person 50 mg. of ethacrynic acid and 500 mg. of acetazolamide.

5. A pharmaceutical preparation for achieving diuresis in a person suffering from Water retention, which involves a compound of (A) from 10 to 100 mg. of ethacrynic acid and a compound selected from the class consisting of (B) 10 to 100 mg. of dichlorphenamide and (C) from 100 to 1000 mg. of acetazolamide.

6. A pharmaceutical preparation according to claim 5 which involves a compound of (A) 25 to 50 mg. of ethacrynic acid and a compound selected from the class consisting of (B) 5 to 50 mg. of dichlorphenamide and (C) from 250 to 500 mg. of acetazolamide.

7. A pharmaceutical preparation according to claim 5 which invloves 50 mg. of ethacrynic acid and 50 mg. of dichlorphenamide.

8. A pharmaceutical preparation according to claim 5 which comprises 50 mg. of ethacrynic acid and 500 mg. of acetazolamide.

References Cited UNITED STATES PATENTS 5/1951 Clapp et al 260-294.8 5/1958 Schultz 260-556 LEROY B. RANDALL, Assistant Examiner. 

1. THE METHOD OF ACHIEVING DIURESIS IN A PERSON SUFFERING FROM WATER RETENTION, WHICH INVOLVES ADMINISTERING TO THAT PERSON (A) FROM 10 TO 100 MG. OF ETHACRYNIC ACID AND COADMINISTERING SUBSTANTIALLY SIMULTANEOUSLY THEREWITH A COMPOUND SELECTED FROM THE CLASS CONSISTING OF (B) 10 TO 100 MG. OF DICHLORPHENAMIDE AND (C) FROM 100 TO 1000 MG. OF ACETAZOLAMIDE. 